Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”) [TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”) [I-309, TARC, MIP-1β] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
Small molecules including ureido-substituted cyclic amines, arylalkyl cyclic amines, acyclic diamines, cyclic diamines, 4,4-disubstituted piperidines, 1,2,3,4-tetrahydroisoquinolines, imidazolium compounds, 1,4-disubstituted piperazines, piperidines, bicyclic piperidines, substituted furo [2,3,-B] pyridines, and diazabicyclic compounds have been reported in the literature as antagonists of MCP-1 and/or CCR receptors. For example, Trivedi et al, Ann. Reports Med. Chem. 2000, 35, 191; Shiota et al., WO 99/25686; Shiota et al., WO 00/69815; C. Tarby and W. Moree, WO 00/69820; P. Carter and R. Cherney, WO 02/50019; R. Cherney, WO 02/060859; Matsumoto et al., WO 03/091245; Jiao et al., WO 03/093231; Axten et al., WO 03/101970; Pennell et al., WO 03/105853; Blumberg et al., WO 04/009550; Blumberg et al., WO 04/009588; Toupence et al., WO 04/012671; and Colon-Cruz et al., WO-02/070523. Similarly, MCP-1 and/or CCR receptor antagonistic indolopiperidines quaternary amines, spiropiperidines, 2-substituted indoles and benzimidazoles, pyrazolone derivatives, dialkylhomopiperazines, N,N-dialkylhomopiperazines, bicyclic pyrroles, tetrahydropyranyl cyclopentyl tetrahyropyridopyridines, N-aryl sulfonamides, pyrimidyl sulphone amides, 3,4-diamine-3-cyclobutene-1,2-diones, substituted heterocyclic compounds, substituted benzanilides, bipiperidinyl derivatives, and 5-aryl pentadienamides have been reported in the literature. For example, Forbes et al., Bioorg. Med. Chem. Lett. 2000, 10, 1803; Mirzadegan et al., J. Biol. Chem. 2000, 275, 25562; Baba et al., Proc. Natl. Acad. Sci. 1999, 96, 5698; A. Faull and J. Kettle, WO 00/46196; Barker et al., WO 99/07351; Barker et al., WO 99/07678; Padia et al., U.S. Pat. No. 6,011,052; Connor et al., WO 98/06703; Shiota et al., WO 97/44329; Barker et al., WO 99/40913; Barker et al., WO 99/40914; Jiao et al., WO 03/092568; Fleming et al., WO 03/99773; Habashita et al., WO 04/007472; Ebden et al., WO 04/011443; Taveras et al., WO 04/011418; Bondinell et al., WO 04/010942, WO 04/010943 and WO 04/011427; Albert et al., WO 02/081449; and Carson, et al., Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA, 1999.
However, the foregoing reference compounds are readily distinguished structurally from the present invention by virtue of substantial differences in the terminal functionality, the attachment functionality, the core functionality, and/or nature of the bicyclic ring system. Accordingly, the prior art does not disclose nor suggest the unique combination of structural fragments that embody the novel compounds described herein. Furthermore, the prior art does not disclose or suggest that the compounds of the present invention would be effective as MCP-1 antagonists.